Multiple myeloma (MM) is an almost fatal neoplasia characterized by the accumulation of malignant plasma cells (MMC) in the bone marrow. The profile of DNA methylation in MM comprises genomic global hypomethylation and simultaneous promoter hypermethylation of known or potential tumor suppressor genes (Heuck, 2013; Walker, 2010). Recently, hypermethylation of several potential suppressor genes was demonstrated to be associated with significantly shorter overall survival (Heuck, 2013).
Decitabine (5-aza-2′-deoxycytidine) or 5-azacytidine are both clinically used DNMT inhibitors for the treatment of myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) (Hollenbach, 2010). In MM, clinical trials are ongoing with DNMTi as monotherapy or combined with lenalidomide or dexamethasone (Maes, 2013). Histone deacetylases (HDAC) represent also molecular targets for the treatment of different cancers including MM (Feng, 2008; Khan, 2004; Lavelle, 2001; Mitsiades, 2004; Mitsiades, 2003; Catley, 2003; Kaiser, 2006; Neri, 2012; Neri, 2008; Minami, 2013; Hideshima, 2013). Romidepsin and Vorinostat (SAHA) have been approved by the Food and Drug Administration (FDA) for the treatment of cutaneous T-cell lymphoma (Zhang, 2009) and several HDACi are evaluated in clinical trials in MM (Maes, 2013; Neri, 2012). Proteasome inhibition leading to accumulation of ubiquitinated proteins, affecting unfolded protein response (UPR) and increasing HDAC-mediated aggregosome formation indicated that HDACi and bortezomib combination could be promising in MM (Richardson, 2013; San-Miguel, 2013). Combination of panobinostat/bortezomib/dexamethasone (PANORAMA) and of vorinostat/bortezomib (VANTAGE 088) have been initiated in two large phase III clinical trials (Richardson, 2013; Dimopoulos, 2013). Results of VANTAGE 088 trial shown that association of vorinostat and bortezomib prolonged significantly progression free survival, compared to bortezomib and placebo, in patients with relapsed or refractory MM (Dimopoulos, 2013). However, this combination is associated with toxicity and new treatment schedules should be investigated to increase tolerability and enhance efficacy (Dimopoulos, 2013).
It was reported that HDACi and DNMTi treatment can induce MAGE-A3 in MM, an attractive target for immunotherapy, and facilitate killing by MAGE-A3 specific cytotoxic T lymphocytes (Moreno-Bost, 2011). Recently, Matthews et at investigated the potential of combining HDACi with a BH3-only mimetic (ABT-737), recombinant human TNF-related apoptosis-inducing ligand (rhTRAIL) or 5-azacitidine, in vivo, using the Vk*MYC transgenic MM mouse model (Matthews, 2013). HADCi/rhTRAIL or HDACi/ABT-737 combinations are associated with important drug induced toxicity in vivo. In contrast, HDACi and DNMTi demonstrated a significant reduction of tumor load in vivo and prolonged survival of mice without toxicity (Matthews, 2013). In patients with solid cancers or advanced haematological malignancies, HDACi and DNMTi combination was well tolerated (Bots, 2009) and suggested promising activity in MDS, AML (Bots, 2009; Fandy, 2009; Zhang, 2009) and refractory advanced non-small cell lung cancer (Juergens, 2011). Together, these observations suggest that targeting the aberrant tumor-specific epigenetic program with DNMTi and HDACi treatment could have therapeutic interest in MM. However, identification of biomarkers predictive for sensitivity of MMCs to epigenetic therapies remains an important objective to improve clinical trials. The inventors recently reported gene expression (GEP)-based risk scores to predict the sensitivity of MMC to DNMTi (Moreaux, 2013; Moreaux, 2012) and HDACi (Moreaux, 2013). Since HDACi and DNMTi combination have potential therapeutic value in MM, the inventors searched to build a GEP-based score that could be useful to conduct epigenetic-targeted combination trials.
The identification of biomarkers predictive for sensitivity of MMCs to HDACi and DNMTi combination is an important objective for optimizing these clinical trials. In the present invention, the inventors used gene expression profiling of Multiple Myeloma Cells (MMCs) to build a novel “HDACi/DNMTi score” or “HADMS” that makes it possible identification of patients whose MMCs will be targeted by a combination treatment consisting of at least one DNA methyltransferase inhibitor (DNMTi) with at least one histone deacetylase inhibitor (HDACi).